Viral Etiologies of Hospitalized Acute Lower Respiratory Infection Patients in China, 2009-2013 Luzhao Feng 1. , Zhongjie Li 1. , Shiwen Zhao 2. , Harish Nair 3,4 , Shengjie Lai 1 , Wenbo Xu 5 , Mengfeng Li 6 , Jianguo Wu 7 , Lili Ren 8 , Wei Liu 9 , Zhenghong Yuan 10 , Yu Chen 11 , Xinhua Wang 12 , Zhuo Zhao 13 , Honglong Zhang 1 , Fu Li 6 , Xianfei Ye 10 , Sa Li 1 , Daniel Feikin 14 , Hongjie Yu 1 *, Weizhong Yang 1 * 1 Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Centre for Disease Control and Prevention, Beijing, China, 2 Yunnan Provincial Center for Disease Control and Prevention, Kunming, China, 3 Centre for Population Health Sciences, Global Health Academy, The University of Edinburgh, Edinburgh, United Kingdom, 4 Public Health Foundation of India, New Delhi, India, 5 National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China, 6 Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, China, 7 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China, 8 Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China, 9 Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity, Beijing, China, 10 Shanghai Public Health Clinical Center, Shanghai, China, 11 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China, 12 Gansu Provincial Center for Disease Control and Prevention, Lanzhou, China, 13 Liaoning Provincial Center for Disease Control and Prevention, Shenyang, China, 14 Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America Abstract Background: Acute lower respiratory infections (ALRIs) are an important cause of acute illnesses and mortality worldwide and in China. However, a large-scale study on the prevalence of viral infections across multiple provinces and seasons has not been previously reported from China. Here, we aimed to identify the viral etiologies associated with ALRIs from 22 Chinese provinces. Methods and Findings: Active surveillance for hospitalized ALRI patients in 108 sentinel hospitals in 24 provinces of China was conducted from January 2009-September 2013. We enrolled hospitalized all-age patients with ALRI, and collected respiratory specimens, blood or serum collected for diagnostic testing for respiratory syncytial virus (RSV), human influenza virus, adenoviruses (ADV), human parainfluenza virus (PIV), human metapneumovirus (hMPV), human coronavirus (hCoV) and human bocavirus (hBoV). We included 28,369 ALRI patients from 81 (of the 108) sentinel hospitals in 22 (of the 24) provinces, and 10,387 (36.6%) were positive for at least one etiology. The most frequently detected virus was RSV (9.9%), followed by influenza (6.6%), PIV (4.8%), ADV (3.4%), hBoV (1.9), hMPV (1.5%) and hCoV (1.4%). Co-detections were found in 7.2% of patients. RSV was the most common etiology (17.0%) in young children aged ,2 years. Influenza viruses were the main cause of the ALRIs in adults and elderly. PIV, hBoV, hMPV and ADV infections were more frequent in children, while hCoV infection was distributed evenly in all-age. There were clear seasonal peaks for RSV, influenza, PIV, hBoV and hMPV infections. Conclusions: Our findings could serve as robust evidence for public health authorities in drawing up further plans to prevent and control ALRIs associated with viral pathogens. RSV is common in young children and prevention measures could have large public health impact. Influenza was most common in adults and influenza vaccination should be implemented on a wider scale in China. Citation: Feng L, Li Z, Zhao S, Nair H, Lai S, et al. (2014) Viral Etiologies of Hospitalized Acute Lower Respiratory Infection Patients in China, 2009-2013. PLoS ONE 9(6): e99419. doi:10.1371/journal.pone.0099419 Editor: Oliver Schildgen, Kliniken der Stadt Ko ¨ ln gGmbH, Germany Received January 22, 2014; Accepted May 14, 2014; Published June 19, 2014 Copyright: ß 2014 Feng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the National Key Science and Technology Project on Infectious Disease Surveillance Technique Platform of China (2009ZX10004-201, 2009ZX10004-202, 2009ZX10004-204, 2009ZX10004-206, 2009ZX10004-207, 2009ZX10004-208, 2009ZX10004-209, 2009ZX10004-210, 2009ZX10004-211, 2009ZX10004-212, 2009ZX10004-213, 2012ZX10004-201, 2013ZX10004-202, 2012ZX10004-206, 2012ZX10004-207, 2012ZX10004-208, 2012ZX10004-209, 2012ZX10004-210, 2012ZX10004-211, 2012ZX10004-212, 2012ZX10004-213). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: [email protected] (WY); [email protected] (HY) . These authors contributed equally to this work. Introduction Acute lower respiratory infections (ALRIs) continue to be an important cause of acute illnesses and mortality worldwide (especially in infants and young children) [1–4]. The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) estimates that there were 2.8 million deaths due to lower respiratory infections globally in 2010 (5.3% of the total deaths) [4]. The incidence of ALRIs in children aged less than 5 years is estimated to be 0.22 episodes per child-year, with 11.5% cases PLOS ONE | www.plosone.org 1 June 2014 | Volume 9 | Issue 6 | e99419
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Honglong Zhang1, Fu Li6, Xianfei Ye10, Sa Li1, Daniel Feikin14, Hongjie Yu1*, Weizhong Yang1*
1 Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Centre for Disease Control and Prevention, Beijing, China,
2 Yunnan Provincial Center for Disease Control and Prevention, Kunming, China, 3 Centre for Population Health Sciences, Global Health Academy, The University of
Edinburgh, Edinburgh, United Kingdom, 4 Public Health Foundation of India, New Delhi, India, 5 National Institute for Viral Disease Control and Prevention, Chinese
Center for Disease Control and Prevention, Beijing, China, 6 Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, China,
7 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China, 8 Institute of Pathogen Biology, Chinese Academy of Medical Sciences &
Peking Union Medical College, Beijing, China, 9 Beijing Institute of Microbiology and Epidemiology, State Key Laboratory of Pathogen and Biosecurity, Beijing, China,
10 Shanghai Public Health Clinical Center, Shanghai, China, 11 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of
Medicine, Zhejiang University, Hangzhou, China, 12 Gansu Provincial Center for Disease Control and Prevention, Lanzhou, China, 13 Liaoning Provincial Center for Disease
Control and Prevention, Shenyang, China, 14 Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and
Prevention, Atlanta, Georgia, United States of America
Abstract
Background: Acute lower respiratory infections (ALRIs) are an important cause of acute illnesses and mortality worldwideand in China. However, a large-scale study on the prevalence of viral infections across multiple provinces and seasons hasnot been previously reported from China. Here, we aimed to identify the viral etiologies associated with ALRIs from 22Chinese provinces.
Methods and Findings: Active surveillance for hospitalized ALRI patients in 108 sentinel hospitals in 24 provinces of Chinawas conducted from January 2009-September 2013. We enrolled hospitalized all-age patients with ALRI, and collectedrespiratory specimens, blood or serum collected for diagnostic testing for respiratory syncytial virus (RSV), human influenzavirus, adenoviruses (ADV), human parainfluenza virus (PIV), human metapneumovirus (hMPV), human coronavirus (hCoV)and human bocavirus (hBoV). We included 28,369 ALRI patients from 81 (of the 108) sentinel hospitals in 22 (of the 24)provinces, and 10,387 (36.6%) were positive for at least one etiology. The most frequently detected virus was RSV (9.9%),followed by influenza (6.6%), PIV (4.8%), ADV (3.4%), hBoV (1.9), hMPV (1.5%) and hCoV (1.4%). Co-detections were found in7.2% of patients. RSV was the most common etiology (17.0%) in young children aged ,2 years. Influenza viruses were themain cause of the ALRIs in adults and elderly. PIV, hBoV, hMPV and ADV infections were more frequent in children, whilehCoV infection was distributed evenly in all-age. There were clear seasonal peaks for RSV, influenza, PIV, hBoV and hMPVinfections.
Conclusions: Our findings could serve as robust evidence for public health authorities in drawing up further plans toprevent and control ALRIs associated with viral pathogens. RSV is common in young children and prevention measurescould have large public health impact. Influenza was most common in adults and influenza vaccination should beimplemented on a wider scale in China.
Citation: Feng L, Li Z, Zhao S, Nair H, Lai S, et al. (2014) Viral Etiologies of Hospitalized Acute Lower Respiratory Infection Patients in China, 2009-2013. PLoSONE 9(6): e99419. doi:10.1371/journal.pone.0099419
Editor: Oliver Schildgen, Kliniken der Stadt Koln gGmbH, Germany
Received January 22, 2014; Accepted May 14, 2014; Published June 19, 2014
Copyright: � 2014 Feng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by grants from the National Key Science and Technology Project on Infectious Disease Surveillance Technique Platform ofChina (2009ZX10004-201, 2009ZX10004-202, 2009ZX10004-204, 2009ZX10004-206, 2009ZX10004-207, 2009ZX10004-208, 2009ZX10004-209, 2009ZX10004-210,2009ZX10004-211, 2009ZX10004-212, 2009ZX10004-213, 2012ZX10004-201, 2013ZX10004-202, 2012ZX10004-206, 2012ZX10004-207, 2012ZX10004-208,2012ZX10004-209, 2012ZX10004-210, 2012ZX10004-211, 2012ZX10004-212, 2012ZX10004-213). The funders had no role in study design, data collection andanalysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Co-detection of Multiple Viral EtiologiesAmong the 2032 ALRI patients with co-detection, two viruses
were identified in 1709 cases (84.1% of cases with co-detection),
three viruses were detected in 277 cases (13.6%), and four or more
viruses were detected in 46 cases (Table 2). RSV was the most
frequent etiology in cases with co-detection. RSV and another
respiratory virus were detected in 1296 (53.8%) cases 354 cases
Figure 1. Enrollment of 28,369 hospitalized patients with acute lower respiratory infection tested for seven virus etiologies fromJanuary 1, 2009 to September 30, 2013 in China.doi:10.1371/journal.pone.0099419.g001
Viral Etiologies of ALRI in China
PLOS ONE | www.plosone.org 3 June 2014 | Volume 9 | Issue 6 | e99419
positive in combination with influenza viruses and 272 cases with
PIV. hBoV co-detection (with other viral pathogens) was observed
in 413 (24.2%) of 1709 cases (75% of 551 cases with hBoV mono-
infection).
Temporal Trends of Viral EtiologiesOver the 57-month period, there were clear seasonal peaks for
RSV, influenza, PIV, hBoV and hMPV infections. RSV activity
was observed throughout the year during the 5 year period with an
annual a peak in January–February each year (Figure 5, Panel A).
Similarly Influenza circulation was observed throughout the year
with peaks in autumn-winter. The peaks were higher in 2009
when A(H1N1)pdm09 influenza circulated in worldwide and
Spring (January–March) in 2012, and relatively lower activity was
observed in the post-pandemic seasons of 2010–2011 and 2013
(Figure 5, Panel B). PIV, hBoV and hMPV infections had a similar
pattern of one peak annually, with peak PIV and hMPV infections
observed in late spring (March–May) in most seasons and hBoV
peaking in summer (June–July) (Figure 5, Panels C, E and F).
There were no clear temporal trends for patients infected with
ADV and hCoV (Figure 5, Panels D and G), even when analysis
was stratified by age group (Figure S1 and Figure S2).
Discussion
This study is the first to describe the viral etiologies in
hospitalized ALRI patients using data from sentinel surveillance
sites covering the majority of Chinese provinces over 5 consecutive
years; and based on a standardized surveillance protocol and
laboratory assays. A total of 28,369 hospitalized ALRI patients
were enrolled from 2009–2013, and 36.6% were positive for at
least one virus, which is consistent with published data reported
from China and other countries [13,18,19].
Our findings that RSV was the leading pathogen identified in
young children under two years hospitalized for lower respiratory
tract infections demonstrates that RSV could also be associated
with substantial morbidity and mortality in China, as reported in
studies from other industrialized and developing countries [20–
22]. This finding indicates that prevention strategies for RSV such
immunization when a suitable vaccine is available in the future
could have large public health impact in China. We also
demonstrated that influenza viruses could lead to substantial
burden on health care system especially in a large country like
China with a rapidly aging population especially since influenza
positivity rate was higher in adults and elderly. This is consistent
with the reported estimates of influenza disease burden based on
studies conducted in China and across the world [23–26].
However, influenza vaccination (which confers individual and
herd immunity) has an extremely low coverage rate in China [27].
Figure 2. Location of 81 surveillance hospitals for hospitalized acute lower respiratory infection patients. The red dots indicate thelocation of the surveillance hospitals. A total of 81 hospitals in 22 provinces participate in acute lower respiratory infection surveillance for finalanalysis. The box indicates Spratly Islands in Southern China Sea.doi:10.1371/journal.pone.0099419.g002
Viral Etiologies of ALRI in China
PLOS ONE | www.plosone.org 4 June 2014 | Volume 9 | Issue 6 | e99419
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Viral Etiologies of ALRI in China
PLOS ONE | www.plosone.org 5 June 2014 | Volume 9 | Issue 6 | e99419
Widespread use of influenza vaccine should have a considerable
impact on the influenza disease burden in China. PIV was the
second most common pathogen identified in children aged less
than 2 years. We also observed that ADV was an important virus
associated with ALRI in children. These evidences will be
Figure 3. Average proportions of viral etiologies for hospitalized acute lower respiratory infection patients in 2009–2013 by agegroup.doi:10.1371/journal.pone.0099419.g003
Figure 4. Proportion of viral etiologies for hospitalized acute lower respiratory infection patients by year. A) RSV. B) Influenza. C) PIV.D) ADV. E) hBoV. F) hMPV. Panel G) hCoV. H) Co-detection.doi:10.1371/journal.pone.0099419.g004
Viral Etiologies of ALRI in China
PLOS ONE | www.plosone.org 6 June 2014 | Volume 9 | Issue 6 | e99419
important for China’s public health authorities to guide the
priority for control of infectious diseases.
From a public health perspective, information on seasonality of
pathogens is crucial to inform the timing of interventions,
particularly for a climatically and economically diverse country
as China [28]. China has an intensive national influenza
surveillance network and influenza seasonality in different
epidemiological regions was identified to be used as a basis to
optimize the timing of future vaccination programs [29]. Our
study demonstrates that although respiratory viruses circulate
throughout the year, viruses like RSV, PIV, hBoV and hMPV
have a clear seasonal trend. RSV activity peaked in January–
February each year, and this is consistent with published reports
from other studies in temperate regions where RSV occurred most
frequently in the winter months [6].
Our study had a few limitations. Firstly, only viral pathogens
were detected in our study; bacterial pathogens were not included,
which prevented us from getting comprehensive data on the
pathogens that are associated with ALRIs and mixed viral-
bacterial infections. Secondly, virus (sub)typing was not performed
systematically and (sub)typing data were not collected., These data
are very important and could provide a more comprehensive
picture by age group and seasonality in various regions [28].
Thirdly, further understanding of seasonality of these viral agents
in various climate regions and co-relation with meteorological data
(temperature, rainfall, humidity etc.) will be important to better
understand and describe the epidemiology of these etiologies and
related diseases, and for appropriately timing the use of
interventions, such as influenza vaccines and future RSV vaccines
[30]. Fourthly, this study did not include HRV during the first four
years, which is also one of most common pathogens associated
with ALRI. 5) The importance of viruses as major causes of ALRIs
is becoming increasingly apparent because the sensitivity of
detection techniques has greatly improved and new molecular
tests are increasingly replacing conventional methods. However,
lack of controls limits our ability to infer a causal association and
therefore our results must be interpreted with caution [31,32].
Conclusion
In conclusion, this study provided important background
information concerning the respiratory viral etiologies in China,
based on a large sample size across a vast territory for multiple
seasons. Our findings could serve as robust evidence for public
health authorities for drawing up further plans to prevent and
control of respiratory virus associated ALRIs. The spectrum of
viral etiologies could be helpful to estimate disease burden
associated with these pathogens and to guide the priority for
future research studies and allocate resources to fight infectious
Table 2. Co-detection of multiple viral etiologies in acute lower respiratory infections.
Viral etiologies No. of cases Viral etiologies No. of cases
Two pathogens 1709 (84.1%) FLU+RSV+hBoV 24
FLU+RSV 354 PIV+ADV+hBoV 16
RSV+PIV 272 RSV+ADV+hBoV 15
RSV+ADV 166 RSV+PIV+hCoV 15
RSV+hBoV 144 FLU+RSV+hCoV 11
PIV+hBoV 129 FLU+ADV+hBoV 9
FLU+PIV 99 FLU+PIV+hBoV 7
PIV+ADV 66 RSV+PIV+hMPV 7
RSV+hCoV 63 FLU+PIV+ADV 6
FLU+ADV 59 RSV+hMPV+hBoV 6
FLU+hBoV 55 PIV+ADV+hCoV 5
ADV+hBoV 51 RSV+ADV+hCoV 5
RSV+hMPV 43 ADV+hMPV+hBoV 4
FLU+hCoV 38 FLU+ADV+hCoV 3
PIV+hCoV 37 FLU+hMPV+hBoV 3
FLU+hMPV 26 PIV+ADV+hMPV 3
PIV+hMPV 26 PIV+hCoV+hBoV 3
hMPV+hBoV 18 PIV+hMPV+hBoV 3
ADV+hCoV 16 RSV+ADV+hMPV 3
hCoV+hBoV 16 FLU+hMPV+hCoV 2
hMPV+hCoV 16 FLU+PIV+hCoV 2
ADV+hMPV 15 RSV+hCoV+hBoV 2
Three pathogens 277 (13.6%) ADV+hMPV+hCoV 1
FLU+RSV+PIV 39 FLU+RSV+hMPV 1
RSV+PIV+hBoV 29 RSV+hMPV+hCoV 1
RSV+PIV+ADV 27 4 pathogens 43 (2.1%)
FLU+RSV+ADV 25 5 pathogens 3 (0.1%)
doi:10.1371/journal.pone.0099419.t002
Viral Etiologies of ALRI in China
PLOS ONE | www.plosone.org 7 June 2014 | Volume 9 | Issue 6 | e99419
diseases. RSV is common in very young children and prevention
measures, such as vaccination, could have a large public health
impact. Influenza was most common in adults and influenza
vaccination should be more widespread in China. The seasonality
information could be used as a basis to optimize the timing for the
potential use of appropriate pharmaceutical and nonpharmaceu-
tical interventions against these diseases. These preliminary results
indicate that more robust surveillance data and evaluations are
needed to estimate the disease burden and to understand whether
geographic areas, climate and other environmental factors and
patterns of human behavior influence the timing and severity of
epidemics associated with these viral agents.
Supporting Information
Figure S1 Number and percentage of patients positivefor ADV by age group. A) 0–4 years. B: 5–64 years) C) $65 years.
(TIF)
Figure S2 Number and percentage of patients positive forhCoV by age group. A) 0–4 years. B: 5–64 years) C) $65 years.
information to detect viral etiologies by RT-PCR or PCR in this
study. Table S2. Primers and sequence information to detect viral
etiologies by Real-time RT-PCR or PCR in this study.
(DOCX)
Acknowledgments
We thank staff members of the Department of Science and Education of
the National Health and Family Planning Commission, and the ALRI
surveillance network laboratories and sentinel hospitals in the participating
22 provinces for assistance with field investigation, administration, and
data collection. The views expressed are those of the authors and do not
necessarily represent the policy of the China CDC.
Author Contributions
Conceived and designed the experiments: HY WY. Performed the
experiments: SZ S. Lai WX ML JW LR WL ZY YC XW ZZ HZ.
Analyzed the data: LF ZL S. Lai HZ FL XY S. Li DF HY WY.
Contributed reagents/materials/analysis tools: LF ZL S. Lai HZ FL XY S.
Li HY WY. Wrote the paper: LF ZL HN HY WY.
Figure 5. Number and percentage of patients positive by viral etiology. A) RSV. B) Influenza. C) PIV. D) ADV. E) hBoV. F) hMPV. G) hCoV. H)Co-detection.doi:10.1371/journal.pone.0099419.g005
Viral Etiologies of ALRI in China
PLOS ONE | www.plosone.org 8 June 2014 | Volume 9 | Issue 6 | e99419
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